Globalization and co-morbidity between TB, diabetes, HIV, and metabolic syndrome in sub-Saharan Africa
Authors: Young F, Critchley JA, Johnstone LK, Unwin NC
Reference: Globalization and Health 5(9); March 2009 (open access): http://www.globalizationandhealth.com/content/5/1/9
Summarized by: Vikram Rangan, third year medical student, Duke University School of Medicine, Durham, North Carolina, USA
Tuberculosis (TB) and Human Immunodeficiency Virus (HIV) are two of the most deadly and widespread infectious diseases afflicting persons in sub-Saharan Africa. Summarized below is a review article examining the effect of these two disease processes on one another, their interaction with diabetes mellitus (DM), and the impact of globalization in Africa on these disease processes.
Relationship between diabetes and tuberculosis
The authors cite multiple studies indicating that individuals with diabetes are at increased risk of developing symptomatic tuberculosis. A study in Mumbai, India showed a higher mortality rate from TB in patients simultaneously afflicted with DM. Other studies have demonstrated increased TB severity (evidenced by increased lung cavitations, longer time period in which sputum is positive for TB pathogen, etc.) in patients with DM. The authors cite multiple studies indicating that the likelihood of experiencing symptomatic TB in patients with DM is 1.5-7.8 times greater than in patients without diabetes. This increased risk of symptomatic TB appears to be greatest in younger individuals with DM, and appears to decline in older subjects.
Several proposed mechanisms exist for greater likelihood of symptomatic TB in diabetes patients.
First, DM is known to impair immune function, particularly cell-mediated immunity (the part of the body's immune system that does not rely on antibodies or complement, and targets intracellular pathogens). Research indicates that DM is associated with lower levels of leukocytes (white blood cells, of which there are several types), particularly granulocytes, and Th1 T cells (two specific types of leukocytes). The decreased number of Th1 T cells is particularly important because these cells are responsible for producing important cytokines (signaling molecules used by the immune system) such as IFN-gamma and TNF-alpha. Both of these cytokines are important in activating macrophages (immune cells that are crucial to the body's ability to successfully clear TB infection). Additionally, the authors note that DM frequently results in angiopathy (damaged blood vessels). Pulmonary microangiopathy (damaged lung blood vessels) is thus more likely in patients with DM, and this condition can lead to an increased risk of lung infection., The authors also note the possibility that those with diabetes may have impaired absorption of drugs designed to treat TB, and that the subsequent reduction in efficacy of TB medication may be another factor predisposing them to more severe TB.
While the effect of DM on TB has been well studied, less research exists on the effect of TB on DM. Nonetheless, the authors cite multiple cross sectional studies indicating that being infected with TB is associated with increased likelihood of impaired glucose tolerance and increased rates of DM. However, they note that further longitudinal studies on TB infected patients are needed before a definitive causal relationship between TB and DM can be established. Nonetheless, there are multiple possible explanations for why TB may increase the likelihood of DM. It is possible, for example, that inflammatory cytokines released while mounting an immune response to TB can lead to insulin resistance and decreased insulin production. It also appears that certain TB medications (such as Isoniazid) have hyperglycemic effects that can push individuals towards prediabetes or diabetes.
Relationship between HIV and diabetes
Like TB infection, HIV infection has been identified as a predisposing factor for diabetes and other metabolic abnormalities. The relationship between HIV and DM appears to be more extensively researched than that between TB and diabetes.
Much of the correlation between HIV infection and diabetes is a result of the antiretroviral drugs used to control the HIV virus. Of the five classes of antiretroviral drugs--protease inhibitors (PIs), nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (nNRTIs), fusion inhibitors, and integrase inhibitors--NRTIs, and PIs have been tied particularly strongly with metabolic syndrome:.
The authors note a correlation between antiretroviral therapy (ART) and metabolic syndrome (defined by the authors as central obesity, plus two of the following four signs: raised triglycerides, reduced HDL cholesterol, raised BP, or raised fasting plasma glucose). Specific metabolic abnormalities and risks conferred by HIV include:
- Lipodystrophy: Lipodystrophy is characterized by metabolic abnormalities, insulin resistance, and body fat redistribution. Two studies cited in this review showed that HIV patients taking PIs had an increased risk for it. One study compared healthy people, PI naïve HIV patients, and HIV patients on PIs, and concluded that the HIV positivity and PI use were both tied to an increased risk of lipodystrophy
- Dyslipidemia: Dyslipidemia is characterized by hypertriglycreidemia, hypercholesterolemia, low serum HDL, and features of defective lipoprotein metabolism. One study cited indicates that its prevalence in HIV patients on highly active anti-retroviral therapy (HAART) is 70-80%. While dyslipidemia can be associated with all forms of antiretroviral therapy, the strongest association is with PIs. The presence of dyslipidemia can predispose patients to numerous other medical problems. For example, one study indicated that hypertriglyceridemia associated with PI use is a risk factor for acute pancreatitis.
- Insulin resistance: In a randomized control trial in which ART-naïve patients were randomized to NRTI regimen or NRTI-sparing regimen, it was found that there was reduced insulin sensitivity in NRTI group, but not the NRTI-sparing group. Multiple mechanisms have been proposed for increased insulin resistance as a result of ART use. One is the pro-inflammatory process of HIV itself. A second proposed mechanism is direct ART effects; PIs, for example, are known to block GLUT-4 channels, which are responsible for cellular glucose uptake in response to insulin secretion. Finally, fat redistribution in response to HAART may lead to increased fat deposition in muscle, leading to an impaired ability of skeletal muscle to take up glucose.
- Heart disease: Data from the DAD study (Data collection on adverse events of anti-HIV drugs) show that cardiac abnormalities are more common in HIV patients. According to this study, having metabolic syndrome along with HIV compounded the risk of cardiovascular disease; those with metabolic syndrome and HIV had an approximate 10% likelihood of cardiovascular disease, compared to 5% in HIV patients without metabolic syndrome.
The role of globalization
The process of globalization has brought some benefits to a large number of individuals in sub-Saharan Africa (SSA). In the context of HIV, for example, it has increased access to antiretroviral drugs in several areas with high incidence of the disease. The launch of the 3 by 5 initiative in 2003 by the World Health Organization (WHO) and Joint United Nations Program on HIV/AIDS (UNAIDS) has led to an eight-fold increase in the number of infected individuals in SSA receiving HIV treatment.
However, it also appears that globalization may be tied to an increased rate of diabetes. Indeed, diabetes is an expanding problem in SSA; according to International Diabetes Federation (IDF) estimates, 10.8 million people in the region were diabetic in 2006, and this number is expected to increase to 18.7 million by 2025. Given the previously established relationship between diabetes and TB, this projected increase in diabetes has important implications for efforts to control infectious diseases in the future.
The authors postulate that a significant driver of the increasing prevalence of diabetes is the process of globalization. The trend of urbanization in sub-Saharan Africa has gone hand-in-hand with globalization in recent years; by 2020 the total number of individuals in SSA living in urban areas is expected to double to 487 million. Urbanization is associated with increased levels of obesity, DM, and CV disease. Multiple studies have indicated a 2-5 fold higher prevalence of diabetes in urban areas of SSA compared to rural areas. Indeed, in urban SSA, obesity levels equal those seen in the Western world, likely due to reduced levels of physical activity in an urban setting coupled with the abundance of processed foods. Given that obesity is closely tied to the development of diabetes, it is unsurprising that the prevalence of diabetes is far higher in urban areas as well. Additionally, given that labor migration has been a major driver of HIV spread, it is possible that a continuation of this trend (again, a direct result of globalization) may be linked to increased spread of TB as well.
The authors conclude, "The link between chronic and infectious diseases becomes more important as the epidemiological transition in SSA progresses against a backdrop of globalization.....Many possible pathways of action have been reported.... An awareness of the problems that occur due to the associations seen between chronic and infectious disease should allow us to deal with them more efficiently. More research however is needed upon the mechanisms of action for these risk associations in order for effective prevention or treatment of them to occur and more research needs to be carried out before we truly understand how globalization is impacting upon the associations."